The neurotransmitter 5-hydroxytryptamine (5-HT, serotonin) modulates a wide range of physiological and pathological processes in the central nervous system and periphery, including anxiety, sleep regulation, aggression, feeding and depression (Hoyer et al., Pharmacol. Rev. 46, 157-204, 1994). Both pharmacological characterization and molecular cloning of several 5-HT receptor genes has revealed that 5-HT mediates its diverse physiological actions through a multiplicity of receptor subtypes. These receptors belong to at least two different protein superfamilies: ligand-gated ion channel receptor (5-HT3) and the G-protein-coupled 7-transmembrane receptors (thirteen distinct receptors cloned to date). In addition, within the G-protein-coupled receptors, serotonin exerts its actions through an array of signal transduction mechanisms.
The 5-HT5A receptor is one of 13 G-protein coupled 5-HT receptors and is Gi-α-coupled, inhibiting adenylate cyclase. The receptor protein DNA sequence is not closely related to that of any previously known serotonin receptor, with the best homology being 35% to the human 5-HT1B receptor. It encodes a predicted 357 amino-acid protein, with seven putative transmembrane domains, consistent with that of a G-protein coupled receptor. The sequence is characterized by containing an intron between transmembrane domains V and VI (5-HT5A; Barnes, N. M., & Sharp, T. (1999). A review of central 5-HT receptors and their function. Neuropharmacology 38, 1083-1152; Thomas D. R. 5-HT5A receptors as a therapeutic target. Pharmacol Ther. (2006), 111(3):707-14; Francken B. J., Jurzak M., Vanhauwe J. F., Luyten W. H., Leysen J. E. The human 5-HT5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK 293 cells. Eur. J. Pharmacol. (1998), 361(2-3):299-309. A recent review by Thomas (Pharmacology & Therapeutics, 111, 707-714; 2006) describes the potential therapeutic utility of 5-HT5A receptor ligands for the treatment of circadian rhythm, sleep disturbances, mood disorders, schizophrenia, cognitive disorders and autism.
The human 5-HT5A mRNA is distributed in CNS areas, such as the thalamus, limbic cortex, ventrolateral amygdala, hippocampus, and hypothalamus (Pasqualetti, M., Ori, M., Nardi, I., Castagna, M., Cassano, G. B., & Marazziti, D. (1998). Distribution of the 5-HT5A serotonin receptor mRNA in the human brain. Mol Brain Res 56, 1-8). All of these CNS areas are implicated in either the pathology or treatment of schizophrenia and anxiety. The receptor has not been detected in peripheral organs (Rees, S., Dendaas, I., Foord, S., Goodson, S., Bull, D., Kilpatrick, G., et al. (1994). Cloning and characterisation of the human 5-HT5A serotonin receptor. FEBS Lett 355, 242-246), although it is expressed in rat superior cervical ganglia (Wang, Z. Y., Keith, I. M., Beckman, M. J., Brownfield, M. S., Vidruk, E. H. and Bisgard, G. E. (2000) 5-HT5A receptors in the carotid body chemoreception pathway of rat. Neurosci. Lett. 278, 9-12) and the spinal cord dorsal horn which may indicate the involvement of the 5-HT5A receptor in central motor control, nociception and autonomic function such as stress induced urinary incontinence and overactive bladder (Doly, S., Fischer, J., Brisorgueil, M.-J., Verge, D. and Conrath M. 5-HT5A Receptor Localization in the Rat Spinal Cord Suggests a Role in Nociception and Control of Pelvic Floor Musculature The Journal of comparative neurology 476:316-329 (2004)). Gene association studies investigating the occurrence of several common polymorphisms within the 5-HT5A receptor gene, such as—19G/C which shows allelic association with bipolar affective disorder, unipolar depression and schizophrenia (Birkett, J. T., Arranz, M. J., Munro, J., Osbourn, S., Kerwin, R. W., Collier, D. A., 2000. Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response. Neuroreport 11, 2017-2020). In addition, an allelic association of the polymorphism Pro-15-Ser was found within a large proportion of Japanese schizophrenic patients (Iwata, N., Ozaki, N., Inada, T., & Goldman, D. (2001). Association of a 5-HT5A receptor polymorphism, Pro15Ser, to schizophrenia. Mol Psychiatry 6, 217-219).
Until recently, pharmacological characterisation of the 5-HT5A receptor has been limited due to lack of available selective ligands. However, in 2006 Garcia-Ladona, F. J. et al. 36th Annu. Meet. Soc. Neurosci. (2006), October 14-18, Atlanta, Abstract 33.1 (see also WO 2005082871) reported preclinical evidence that certain selective 5-HT5A receptor antagonists have an antipsychotic profile in animal models of schizophrenia by antagonizing methamphetamine and MK-801-induced hyperlocomotion, apomorphine-induced climbing and mescaline-induced scratching, while reversing disrupted social interaction (Jongen-Relo et al., 2006). Supporting evidence included, a reduction in the number of spontaneously active midbrain dopaminergic neurons observed after subchronic A-763079 treatment, suggesting potential antipsychotic-like activity. Data indicating that their 5-HT5A receptor antagonists increase ACh levels in mPFC (Drescher, K. U. et al. 36th Annu. Meet. Soc. Neurosci. (2006), October 14-18, Atlanta, Abstr. 33.2), and suggesting the potential efficacy of 5-HT5A receptor antagonists against the cognitive deficits associated with different psychiatric disorders, in particular schizophrenia and psychosis were also presented. Thomas et al. (2006), (SB-699551-A (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(40-{[(2 phenylethypamino]methyl}-4 biphenylyl)methyl]propanamide dihydrochloride), a novel 5-ht5A receptor-selective antagonist, enhances 5-HT neuronal function: Evidence for an autoreceptor role for the 5-ht5A receptor in guinea pig brain. Neuropharmacology. 2006 September; 51(3):566-77) recently published microdialysis data demonstrating 5-HT5A receptor antagonism of 5-CT-induced guinea-pig raphé neuronal firing and implying that the receptor may also act as an autoreceptor, with similar effects of those produced by anxiolytics and antidepressants. No behavioural data has been provided mainly due to species limitations. Furthermore, 5-HT5A receptor is expressed in the hamster suprachiasmatic nucleus a region known to be involved in circadian timing circuitry (Duncan, M. J., Jennes, L., Jefferson, J. B., Brownfield, M. S. (2000). Localization of serotonin5A receptors in discrete regions of the circadian timing system in the Syrian hamster. Brain Research 869, 178-185). Activation of both 5-HT5A and 5-HT, receptors can produce phase advances of the circadian clock in-vitro (Sprouse J, Reynolds L, Braselton J, Schmidt A. Serotonin-induced phase advances of SCN neuronal firing in vitro: a possible role for 5-HT5A receptors? Synapse 2004 November; 54(2):111-8).